At least 65% of individuals with diabetes die of some form of heart disease or stroke. This occurs despite effective treatments for certain cardiovascular risk factors, such as high low-density lipoprotein (LDL) cholesterol and hypertension. High-density lipoprotein (HDL) cholesterol is a major cardiovascular risk factor that is often low among individuals with type 2 diabetes. Behavioral interventions targeting weight and/or physical activity are well known to improve HDL. At the same time, however, genome-wide association studies (GWAS) have been successful in identifying markers associated with HDL and twin studies suggest that HDL response to behavioral intervention is heritable. In this application, we propose to determine whether well established genetic predictors of HDL also predict individual differences in HDL response to weight loss and physical activity intervention. These efforts will help identify individuals who may be resistant to HDL change in response to behavioral efforts and may lead to tailoring of interventions to optimize treatment for these individuals. Specifically, we will determine whether HDL genes (CETP, LPL, LIPC, ABCA1 and LIPG) interact with lifestyle intervention in predicting change in HDL at year 1 and 4 of the Look AHEAD trial, an NIH-funded, multi-center randomized controlled trial with the primary goal of determining whether weight loss achieved through an intensive lifestyle intervention can reduce cardiovascular morbidity and mortality among persons with type 2 diabetes (grant #DK056992). At year 1, participants assigned to Intensive Lifestyle Intervention (ILI), focusing on changes in diet and physical activity (N = 2,496; 97.1% follow-up), lost significantly more weight and showed greater improvements in fitness than individuals assigned to the Diabetes Support and Education (DSE) group (N= 2,463, 95.7% follow-up), who received diabetes support and education groups alone. The weight loss and improved fitness in the ILI at year 1 produced a significantly greater increase in HDL (7.8%), relative to DSE (2.9%). Greater increases in HDL in ILI relative to DSE are also seen at year 4. Consent for genetic analyses was provided by 3,990 participants. Genotype data for HDL markers identified from genome-wide association studies and from the IBC chip, a genotyping platform including 50,000 SNPs from ~2,600 genes relevant to cardiovascular disease, lipid metabolism, diabetes and obesity, will allow us to test our central hypothesis that genes that contribute to variability in HDL will interact with lifestyle treatment to influence changes in HDL following intensive weight loss and physical activity intervention.